Feline Mammary Fibroadenomatous Hyperplasia

Feline mammary fibroadenomatous hyperplasia (FMFH), also known as feline mammary hyperplasia or fibroepithelial hyperplasia, is a benign, non-neoplastic proliferative disorder of the mammary gland in cats, characterized by rapid, often dramatic enlargement of one or multiple mammary glands. The condition is hormonally driven, primarily by progesterone, and occurs most commonly in young, intact female cats during the luteal phase of the estrous cycle or in cats of either sex treated with exogenous progestins. The proliferation involves both the epithelial and stromal components of the mammary gland, with a prominent fibrovascular stroma and ductal hyperplasia. FMFH is distinct from mammary neoplasia in that it is reversible upon withdrawal of the hormonal stimulus or ovariohysterectomy, and it does not metastasize. The disease is classified as a benign, non-inflammatory, proliferative mammary gland disorder, and it is the most common cause of rapid mammary gland enlargement in young female cats. The condition can be unilateral or bilateral, and it may affect any of the four pairs of mammary glands, though the inguinal glands are most frequently involved. The clinical presentation ranges from mild, localized swelling to massive, pendulous, ulcerated masses that can interfere with locomotion and cause significant discomfort. FMFH is a significant clinical entity in feline practice due to its alarming appearance, potential for skin necrosis and secondary infection, and the need for prompt hormonal and/or surgical intervention.

The primary etiological factor in FMFH is progesterone, which acts on the mammary gland to induce proliferation of both epithelial and stromal elements. Progesterone is produced by the corpus luteum during the luteal phase of the estrous cycle in intact queens, and it is also present in exogenous progestin formulations used for estrus suppression or treatment of behavioral disorders. The condition is most commonly associated with endogenous progesterone during the luteal phase (diestrus), which typically occurs after ovulation, whether spontaneous or induced. In cats, ovulation is induced by mating, but can also occur spontaneously in some individuals. Exogenous progestins, such as medroxyprogesterone acetate, megestrol acetate, and proligestone, are well-documented causes of FMFH, and the condition can occur in both intact and neutered cats of either sex when these drugs are administered. The molecular mechanism involves progesterone binding to progesterone receptors (PR) in the mammary gland, which are upregulated by estrogen. Progesterone stimulates the expression of growth factors, including epidermal growth factor (EGF) and insulin-like growth factor (IGF), which promote cellular proliferation. Additionally, progesterone may induce the expression of the progesterone receptor itself, creating a positive feedback loop. The stromal component is particularly responsive to progesterone, leading to the characteristic fibroadenomatous proliferation. In some cases, growth hormone (GH) may also play a role, as progesterone can stimulate GH secretion from the mammary gland in cats, further promoting hyperplasia. The condition is not infectious, and no bacterial or viral agents have been implicated in the primary pathogenesis. However, secondary bacterial infection can occur in ulcerated or necrotic mammary tissue.

FMFH is a disease of cats, with a predilection for young, intact females. The majority of cases occur in cats between 1 and 2 years of age, although it can occur in kittens as young as 6 months and in older cats. The condition is rare in neutered cats unless they have received exogenous progestins. Breed predisposition has not been clearly established, but some reports suggest that Siamese, Burmese, and domestic shorthair cats may be overrepresented, possibly due to their popularity and breeding practices. The incidence is higher in intact females during the luteal phase of the estrous cycle, which in the Northern Hemisphere typically occurs from spring to fall, but can occur year-round in indoor cats. The use of progestin contraceptives or estrus suppression drugs is a significant risk factor, and the condition can occur in male cats treated with progestins for behavioral problems such as urine spraying. The disease is not associated with parity, as it can occur in nulliparous and primiparous queens. The overall incidence is not well documented, but it is considered a relatively common condition in feline practice, particularly in regions where progestin use is prevalent. The condition is benign and does not predispose to mammary neoplasia, but it can cause significant morbidity due to the size and ulceration of the mammary glands.

The pathophysiology of FMFH is centered on the hormonal stimulation of the mammary gland by progesterone. During the luteal phase, the corpus luteum secretes progesterone, which binds to progesterone receptors (PR) in the mammary epithelium and stroma. Estrogen, which is elevated during proestrus and estrus, upregulates PR expression, making the gland more sensitive to progesterone. Progesterone induces the proliferation of both the epithelial cells lining the ducts and the surrounding fibrous stroma. The stromal proliferation is particularly prominent, leading to the formation of a fibroadenomatous mass. The growth is rapid and can be massive, with the gland increasing in size several-fold within days to weeks. The overlying skin may become stretched, leading to ischemia, necrosis, and ulceration. Secondary bacterial infection can then occur, causing suppurative inflammation and systemic signs. The exact molecular pathways involve the activation of PR, which translocates to the nucleus and modulates gene expression. Progesterone also stimulates the local production of growth hormone (GH) in the mammary gland, which acts in an autocrine or paracrine manner to promote cell proliferation. Additionally, progesterone may upregulate the expression of growth factors such as EGF and IGF, which further stimulate mitosis. The condition is reversible if the progesterone source is removed, either by ovariohysterectomy (removing the corpus luteum) or by discontinuing exogenous progestins. However, if the condition is severe and chronic, fibrosis and necrosis may be irreversible, requiring surgical excision. The disease does not metastasize, and malignant transformation is extremely rare, if it occurs at all.

Several factors predispose cats to FMFH. The most significant is the presence of progesterone, either endogenous or exogenous. Intact female cats in the luteal phase of the estrous cycle are at risk, particularly if they are young (under 2 years of age). The condition is more common in cats that have been mated or have ovulated, as ovulation induces corpus luteum formation. However, spontaneous ovulation can occur in some cats, so even unmated queens can develop the condition. Exogenous progestin administration is a major risk factor, and the risk increases with the dose and duration of treatment. Cats treated with long-acting injectable progestins, such as medroxyprogesterone acetate, are at higher risk than those treated with oral progestins. Male cats treated with progestins for behavioral issues are also at risk. Other predisposing factors include obesity, which may increase the risk due to increased adipose tissue and peripheral conversion of androgens to estrogen, and possibly genetic factors, as certain breeds may be more susceptible. The condition is not associated with pregnancy or lactation, and it can occur in nulliparous cats. Stress and poor nutrition may also contribute, but these are not well-established. Overall, the primary predisposing factor is hormonal imbalance, with progesterone being the key driver.

The clinical signs of FMFH are primarily related to the rapid enlargement of the mammary glands. The condition typically presents with acute, bilateral, or unilateral swelling of one or more mammary glands, often involving the inguinal glands. The glands are firm, well-circumscribed, and may be painful on palpation. The overlying skin may be erythematous, warm, and stretched, and in severe cases, it may become ulcerated and necrotic. The masses can grow to a large size, sometimes reaching 10-15 cm in diameter, and may interfere with locomotion, causing a waddling gait. The cat may show signs of discomfort, such as lethargy, decreased appetite, and reluctance to move. If secondary bacterial infection occurs, there may be purulent discharge from the ulcerated areas, and the cat may develop fever and systemic signs of sepsis. In some cases, the mammary glands may be so enlarged that they cause respiratory distress due to pressure on the thorax. The condition is not associated with systemic signs in the absence of infection, and the cat may otherwise appear healthy. The clinical signs can be alarming to owners due to the rapid onset and dramatic appearance. It is important to note that FMFH can occur in male cats, and the clinical signs are similar, with enlargement of the mammary glands. The condition is not associated with lactation, and there is no milk production.

The differential diagnoses for FMFH include other causes of mammary gland enlargement in cats. These include: 1) Mammary neoplasia (adenocarcinoma, adenoma, fibroadenoma): Mammary tumors are more common in older cats (over 10 years) and are often firm, irregular, and may be fixed to underlying tissues. They can be distinguished by histopathology. 2) Mastitis: This is an infection of the mammary gland, usually occurring during lactation, and is associated with systemic signs such as fever, lethargy, and pain. The gland is often hot, swollen, and painful, and there may be purulent or bloody milk. 3) Galactostasis: This is the accumulation of milk in the mammary glands, usually during weaning, and is not associated with rapid proliferation. 4) Trauma or hematoma: A history of trauma and the presence of bruising or swelling may suggest a hematoma. 5) Abscess: A localized collection of pus, often associated with a wound or bite, and may be fluctuant. 6) Cystic hyperplasia: This is a benign condition that can occur in older cats and is characterized by multiple cysts. 7) Foreign body reaction: A foreign body such as a grass awn can cause a localized inflammatory mass. 8) Granulomatous disease: Fungal or mycobacterial infections can cause granulomatous masses. 9) Lipoma: A benign fatty tumor that is soft and mobile. 10) Skin tumor: Tumors of the skin overlying the mammary gland, such as mast cell tumors, can mimic mammary gland enlargement. The key differentiating features include the age of the cat, the rapidity of onset, the presence of hormonal exposure, and the results of cytology and histopathology. FMFH is typically seen in young cats with a history of progestin exposure or during the luteal phase, and the masses are often bilateral and rapidly growing.

The diagnostic algorithm for FMFH begins with a thorough history and physical examination. The history should include the cat's age, sex, reproductive status, estrous cycle stage, and any history of progestin administration. The physical examination should include a complete evaluation of the mammary glands, noting the size, consistency, symmetry, and presence of ulceration or discharge. The following steps are recommended: 1) Perform a fine-needle aspirate (FNA) of the affected mammary gland for cytology. FMFH typically shows a mixed population of epithelial cells and spindle-shaped stromal cells, with no evidence of malignancy. 2) Obtain a biopsy for histopathology if the cytology is inconclusive or if neoplasia is suspected. Histopathology is the gold standard for diagnosis and will show proliferation of both epithelial and stromal elements. 3) Perform a serum progesterone assay to confirm the luteal phase or exogenous progestin exposure. Progesterone levels >2 ng/mL are consistent with luteal phase. 4) Perform abdominal ultrasonography to evaluate the ovaries and uterus. In intact females, the presence of a corpus luteum confirms the luteal phase. 5) Perform a complete blood count and serum biochemistry to assess for secondary infection or systemic illness. 6) If the cat is intact, recommend ovariohysterectomy as both a diagnostic and therapeutic measure, as removal of the ovaries will eliminate the source of progesterone. 7) If the cat is on exogenous progestins, discontinue the drug. 8) In cases of ulceration, perform bacterial culture and sensitivity testing to guide antibiotic therapy. 9) Consider thoracic radiography if metastasis is suspected, although FMFH is benign and does not metastasize. The diagnostic algorithm is straightforward, and the diagnosis is often made based on the clinical presentation and response to hormonal withdrawal.

Laboratory findings in FMFH are typically non-specific but can support the diagnosis. Serum progesterone levels are elevated in intact females during the luteal phase, with levels >2 ng/mL indicating active luteal function. In cats on exogenous progestins, progesterone levels may be elevated or may be within the normal range depending on the drug and assay. Complete blood count may be normal in uncomplicated cases, but may show leukocytosis with a left shift if secondary bacterial infection is present. Serum biochemistry is usually within normal limits, but may show elevated liver enzymes if the cat has been on long-term progestin therapy. Vaginal cytology is not typically performed in the diagnosis of FMFH, but if performed during the luteal phase, it would show a predominance of intermediate and parabasal cells, with few superficial cells. Urinalysis is usually normal. Bacterial culture of any discharge from ulcerated glands may reveal secondary pathogens such as Staphylococcus, Streptococcus, or Escherichia coli. Histopathology of a biopsy sample is the definitive diagnostic test and will show proliferation of both epithelial and stromal elements, with a characteristic fibroadenomatous pattern. The epithelial component may show ductal hyperplasia, and the stroma is composed of spindle-shaped fibroblasts with varying degrees of collagen deposition. There is no evidence of malignancy, such as cellular atypia or invasion. Immunohistochemistry for progesterone receptors may be positive, confirming the hormonal etiology.

Imaging modalities are useful in the evaluation of FMFH, primarily to assess the extent of the disease and to rule out other conditions. Abdominal ultrasonography is the most commonly used imaging modality. In intact females, ultrasonography can identify the presence of a corpus luteum in the ovaries, which confirms the luteal phase. The mammary glands themselves can be evaluated, and FMFH typically appears as a well-defined, homogeneous, hypoechoic mass with no evidence of invasion into surrounding tissues. The skin may be thickened, and there may be fluid accumulation if there is secondary infection. Ultrasonography can also be used to guide fine-needle aspiration or biopsy. Thoracic radiography is recommended if there is concern for metastasis, although FMFH is benign and does not metastasize. Radiographs of the mammary glands are not typically helpful, as the soft tissue masses are not well visualized. Computed tomography (CT) and magnetic resonance imaging (MRI) are not routinely used but may be helpful in complex cases to assess the extent of the disease and to plan surgical excision. Vaginoscopy is not relevant to the diagnosis of FMFH. Overall, imaging is not essential for the diagnosis, but it can be helpful in confirming the reproductive status and in ruling out other conditions.

Cytology and histopathology are essential for the definitive diagnosis of FMFH. Fine-needle aspiration (FNA) cytology is a minimally invasive technique that can be performed in the clinic. The aspirate typically yields a moderately cellular sample with clusters of benign epithelial cells and spindle-shaped stromal cells. The epithelial cells are uniform, with round to oval nuclei and moderate cytoplasm, and there is no evidence of malignancy, such as anisocytosis, anisokaryosis, or prominent nucleoli. The stromal cells are elongated and may be arranged in bundles. The background may contain red blood cells and occasional inflammatory cells if there is secondary infection. Histopathology is the gold standard and is obtained via a biopsy, either incisional or excisional. The histopathological features of FMFH include a well-demarcated, non-encapsulated mass composed of proliferating ducts and stroma. The ducts are lined by a single or double layer of cuboidal to columnar epithelial cells, and there is often ductal ectasia. The stroma is composed of spindle-shaped fibroblasts with varying amounts of collagen, and it is often myxoid or edematous. There is no evidence of invasion into the surrounding tissue, and the mitotic index is low. Special stains, such as Masson's trichrome, can highlight the collagen in the stroma. Immunohistochemistry for progesterone receptors is often positive, confirming the hormonal etiology. The histopathological features are distinct from mammary neoplasia, which would show cellular atypia, invasion, and a high mitotic index.

The treatment of FMFH is aimed at removing the source of progesterone and managing the clinical signs. The primary treatment is ovariohysterectomy (OHE) in intact females, which removes the ovaries and thus the corpus luteum, leading to a rapid decrease in progesterone levels. In cats on exogenous progestins, the drug should be discontinued immediately. In some cases, medical management with progesterone receptor antagonists, such as aglepristone, may be used. Aglepristone is a synthetic antiprogestin that competitively binds to the progesterone receptor, blocking the effects of progesterone. The recommended dosage is 10 mg/kg subcutaneously on days 1, 2, and 7, and then once weekly until regression is observed. This treatment is particularly useful in breeding queens where OHE is not desired, or in cases where surgery is not immediately feasible. In addition to hormonal therapy, supportive care is essential. If the mammary glands are ulcerated or infected, appropriate antibiotics should be administered based on culture and sensitivity. Pain management with non-steroidal anti-inflammatory drugs (NSAIDs) or opioids may be necessary. In severe cases, surgical excision of the affected mammary glands (mastectomy) may be required, especially if there is extensive necrosis or if the masses do not regress with medical therapy. However, mastectomy is generally avoided in young breeding queens, and medical management is preferred. The prognosis is excellent with appropriate treatment, and the mammary glands typically return to normal size within 2-4 weeks after OHE or aglepristone therapy. In cases where the condition is severe and chronic, there may be residual fibrosis, but this is usually cosmetic and does not affect the cat's health. It is important to monitor the cat closely during treatment, as rapid regression can cause fluid shifts and electrolyte imbalances, although this is rare.

The prognosis for FMFH is excellent with appropriate treatment. The condition is benign and reversible, and the majority of cats respond well to ovariohysterectomy or aglepristone therapy. The mammary glands typically regress within 2-4 weeks, and the cat returns to normal health. The prognosis is worse if the condition is complicated by secondary infection, ulceration, or necrosis, but even these cases can be managed with antibiotics and supportive care. The prognosis for future fertility is good in cats that are treated with aglepristone and do not undergo OHE, as the reproductive tract is not affected. However, there is a risk of recurrence if the cat is exposed to progesterone again, either through subsequent estrous cycles or exogenous progestins. Therefore, it is recommended to avoid progestin use in cats that have had FMFH. The long-term prognosis is excellent, and there is no evidence that FMFH predisposes to mammary neoplasia. Negative prognostic indicators include severe necrosis, systemic infection, and delayed treatment. Overall, the prognosis is very good, and the condition is rarely life-threatening.

Follow-up care for FMFH is important to ensure complete resolution and to monitor for recurrence. After ovariohysterectomy, the cat should be re-examined within 2 weeks to assess the regression of the mammary glands. The surgical incision should be monitored for signs of infection. If aglepristone is used, the cat should be re-examined weekly until the mammary glands have returned to normal size. Serum progesterone levels can be monitored to confirm the effectiveness of the treatment, although this is not always necessary. In cats that are not ovariohysterectomized, it is important to monitor the estrous cycle and to avoid progestin administration. If the cat is intended for breeding, it is recommended to wait until the mammary glands have fully regressed before allowing mating. Serial ultrasonography can be used to monitor the ovaries and uterus, but this is not routinely required. The owner should be educated about the signs of recurrence and the importance of avoiding progestins. In cases where mastectomy was performed, the surgical site should be monitored for healing and complications. Overall, the follow-up is straightforward, and the prognosis is excellent.

Clinical pearls: 1) FMFH is a diagnosis of exclusion, and a fine-needle aspirate can quickly differentiate it from neoplasia. 2) Aglepristone is a valuable tool for treating FMFH in breeding queens, as it preserves fertility. 3) Ovariohysterectomy is the definitive treatment in non-breeding cats and results in rapid regression. 4) Always check for a history of progestin use, as this is a common cause. 5) The condition can occur in male cats, so do not rule it out based on sex. 6) The rapid growth can be alarming, but the condition is benign and reversible. Pitfalls: 1) Do not mistake FMFH for mammary neoplasia and perform an unnecessary mastectomy. 2) Do not delay treatment, as severe cases can lead to skin necrosis and secondary infection. 3) Do not use progestins in cats with a history of FMFH. 4) Do not forget to rule out pregnancy in intact females, as the luteal phase is a normal part of the estrous cycle. 5) Do not overlook the possibility of exogenous progestin administration in neutered cats. 6) Do not assume that the condition will resolve without treatment, as it can persist and worsen.

The primary medical treatment for FMFH is aglepristone, a progesterone receptor antagonist. The recommended protocol is 10 mg/kg subcutaneously on days 1, 2, and 7, and then once weekly until regression is observed. This protocol is based on studies by Fieni et al. and others. In addition, supportive care may include: 1) Antibiotics: If secondary bacterial infection is present, a broad-spectrum antibiotic such as amoxicillin-clavulanate (12.5-25 mg/kg PO q12h) or cefazolin (22 mg/kg IV q8h) should be administered based on culture and sensitivity. 2) Pain management: NSAIDs such as meloxicam (0.1 mg/kg PO q24h) or buprenorphine (0.01-0.02 mg/kg IV/IM q8-12h) can be used. 3) Fluid therapy: If the cat is dehydrated or in shock, intravenous fluids such as lactated Ringer's solution at a rate of 40-60 mL/kg/day should be administered. 4) In cases of severe ulceration, topical wound care with antiseptic solutions and bandaging may be necessary. 5) If the cat is intact and not intended for breeding, ovariohysterectomy is the treatment of choice. 6) In cases where aglepristone is not available, some clinicians have used cabergoline (5 mcg/kg PO q24h) to reduce prolactin levels, but this is less effective. 7) Prostaglandin F2alpha (dinoprost) is not recommended in cats due to the risk of side effects. The use of exogenous progestins should be strictly avoided in cats with a history of FMFH.

The literature on FMFH is limited but informative. A landmark study by Fieni et al. (2005) evaluated the use of aglepristone in the treatment of FMFH in 12 cats and found that 10 mg/kg on days 1, 2, and 7 resulted in complete regression in all cases within 2-4 weeks. Another study by Wehrend et al. (2001) reported successful treatment with aglepristone in a cat with FMFH. A retrospective study by Misdorp (2002) reviewed the histopathological features of FMFH and confirmed its benign nature. The use of ovariohysterectomy as a treatment is well-established, and a study by Johnston et al. (2001) in the textbook Canine and Feline Theriogenology recommends OHE as the treatment of choice in non-breeding cats. The role of progesterone in the pathogenesis is supported by studies showing that progestin administration can induce FMFH in cats (e.g., a study by Hayden et al., 1981). The condition is also discussed in the BSAVA Manual of Small Animal Reproduction (England & von Heimendahl, 2010), which provides guidelines for diagnosis and treatment. Overall, the evidence supports the use of aglepristone as a safe and effective treatment for FMFH, and OHE as a definitive treatment. There are no large-scale randomized controlled trials, but the existing literature is consistent.